MS Abstracts MRI2g4

Conventional Magnetic Resonance Imaging (MRI) can improve accuracy in the diagnosis of Multiple Sclerosis (MS). Metrics derived from conventional MRI are now routinely used to detect therapeutic effects and extend clinical observations.

HyperIntense lesions on T₂-weighted MRI scans are related primarily to increased water content and thus cannot distinguish between Inflammation, Edema, DeMyelination, Wallerian Degeneration, and Axonal loss.

In addition, T₂-weighted and post-contrast images are not sufficiently sensitive to detect occult disease affecting Normal-Appearing Gray and White Matter.

They do not show a reliable correlation with clinical measures of disability and do not provide a complete assessment of therapeutic outcomes.

In the past few years a host of advanced MRI techniques and analysis methods have been introduced for the assessment of MS.

These MRI techniques appear to have better reliability as surrogate markers for monitoring the pathologic processes that most likely are related to disease activity and clinical progression.

They are able to reveal a range of tissue changes that include Edema, Inflammation, DeMyelination, Axonal loss, and NeuroDegeneration.

Therefore, in a disease with a high degree of longitudinal variability of clinical signs and symptoms within and between patients, and with no current adequate biological markers of disease progression.

Non-conventional MRI techniques provide a powerful tool to non-invasively study pathological substrates of overt lesions and Normal-Appearing Brain Tissue.

In particular, the use of these techniques is promising in elucidating mechanisms underlying the accumulation of tissue damage, repair and functional reorganization of Neural Pathways in patients with MS.

A growing body of evidence indicates that irreversible tissue destruction including Axonal and Neuronal Degeneration is a key component of the Multiple Sclerosis (MS) disease process.

Magnetic Resonance Imaging (MRI) is a powerful technique that can be combined with semiautomated or automated computer assisted analysis approaches to detect progressive Atrophy of the Brain and Spinal Cord with high sensitivity and reproducibility.

The PathoPhysiology of Central Nervous System (CNS) Atrophy in MS is unknown but likely represents an epiphenomenon related to the effects of inflammation.

Including chronic DeMyelination, Axonal injury, Neuronal loss and Wallerian Degeneration.

Other factors that may contribute to Tissue Atrophy include injury to the Normal-Appearing Gray and White Matter by mechanisms such as loss of Growth Factors, Altered Electrical Conduction and pathologic Iron deposition.

Prospective studies have suggested that Atrophy in MS is predicted by previous inflammatory activity as measured by overt MRI lesions.

Gadolinium (Gd)-enhancing lesions have shown a particularly strong predictive value in some but not all longitudinal studies of Brain Atrophy.

Brain Atrophy has also been related in cross-sectional and longitudinal studies to T₂-HypoIntense lesions in deep Gray Matter, suggesting a link between tissue Iron deposition and Atrophy.

The measurement of Brain Atrophy seems to be of growing clinical relevance as a biomarker of the MS disease process.

Atrophy should now be included as a secondary endpoint in trials of therapies aimed at limiting disease progression.

Currently available Anti-Inflammatory ImmunoModulatory agents and ImmunoSuppressive treatments, while effective at preventing clinical deterioration, have shown at best partial effects in preventing CNS Atrophy.

Thus, there is a need to further validate Atrophy as an outcome measure and ultimately develop treatment strategies that will protect against the destructive aspects of the disease process.

This should in turn lead to better long term Neurologic functioning and a better quality of life for patients with MS.

This article focuses on the various Magnetic Resonance Imaging metrics currently used in Multiple Sclerosis and discusses how they relate to Central Nervous System Atrophy.

The authors discuss the significance of T₂ lesion burden, Gray Matter damage, T₁ HypoIntense lesions (black holes), contrast-enhanced lesions, Magnetization Transfer imaging, Diffusion imaging, and Magnetic Resonance Spectroscopy.

These Magnetic Resonance Imaging surrogates exhibit different sensitivities for each of the underlying pathogenic processes of Multiple Sclerosis.

By exploiting the complementary nature and varying sensitivities of these Magnetic Resonance Imaging surrogates, it is possible to create a more comprehensive picture of the degenerative process of Multiple Sclerosis.

Objective
To test the sensitivity of Whole-Brain T₁ relaxometry to the evolution of pathological changes in Multiple Sclerosis (MS).

Background
T₁-weighted HypoIntense lesion load in the Brains of patients with MS is associated with Axonal loss.

Other work has shown that T₁ measurements may provide information complementary to existing imaging techniques, such as Magnetization Transfer Imaging.

Methods
The authors studied 14 MS patients twice over a median time interval of 19.5 months (range, 14-22 months).

Structural images and Whole-Brain T₁ maps using a novel rapid-scanning technique (3 min/study) were performed at 3 T.

Analysis focused on defining changes separately in the lesional and Normal-Appearing White Matter (NAWM) and in the Cortical Gray Matter.

Results
At baseline, there was an inverse relationship between disease duration and the NAWM T₁ Histogram peak height (r = -0.75, P = .03).

The total White Matter T₁ Histogram peak height decreased over time (P < .001). This could be accounted for by changes in the NAWM (P < .03).

There also was a decrease (6%) in the mean (11 of 14 patients, P = .004) and in the median (7%) (13 of 14 patients, P < .001) NeoCortical Gray Matter T₁ over the follow-up period.

Conclusions
Brain T₁ maps can be generated quickly and are sensitive to pathological changes over time.

T₁ values in both the Gray and the White Matter at the baseline visit were related to disease duration, suggesting that the T₁ changes are clinically relevant.

Although the absolute values will be different, it is likely that similar changes will be able to be detected at 1.5 T.

The role of T₁ measurement as a Magnetic Resonance Imaging outcome measure in clinical trials now should be explored.

Quantitative evaluation of Brain Magnetic Resonance Imaging (MRI) scans is now an accepted part of the trial of new putative treatments for Multiple Sclerosis (MS).

However, conventional MRI is not pathologically specific, and it does not reveal the details of the pathological processes that underlie the progression of the disease.

Magnetization Transfer (MT) imaging is a relatively new quantitative technique that appears to offer some pathological specificity, and can be used to monitor the changes over time in both individual lesions and the Central Nervous System as a whole.

This paper considers the case for incorporating MT imaging into new clinical trials, so that the utility of MT for monitoring the modification of MS progression by treatment can be assessed.

Specific guidelines for implementing MT imaging as part of a large multicenter clinical trial are given, and practical considerations when planning such a trial are detailed.

It is anticipated that MT imaging will be incorporated into many new trials in the near future.

Copyright 2003 Wiley-Liss, Inc.

Different MRI techniques are used to investigate Multiple Sclerosis (MS) in vivo. The pathological specificity of these techniques is poorly understood, in particular their relationship to DeMyelination and Axonal loss.

The aim of this study was to evaluate the pathological substrate of high field MRI in post-mortem (PM) Spinal Cord (SC) of patients with MS. MRI was performed in PMSCs of four MS patients and a healthy subject on a 7 Tesla machine.

Quantitative MRI maps (PD; T₂; T₁; Magnetization Transfer Ratio, MTR; Diffusion weighted imaging) were obtained.

After scanning, the Myelin content and the Axonal density of the specimens were evaluated NeuroPathologically using quantitative techniques.

Myelin content and Axonal density correlated strongly with MTR, T₁, PD, and Diffusion Anisotropy, but only moderately with T₂ and weakly with the average Apparent Diffusion Coefficient.

Quantitative MR measures provide a promising tool to evaluate components of MS pathology that are clinically meaningful.

Further studies are warranted to investigate the potential of new quantitative MR measures to enable a distinction between Axonal loss and DeMyelination and between DeMyelinated and ReMyelinated lesions.

Background
One of the diagnostic imaging hallmarks of MS is the uptake of IV administered contrast material in new lesions in the Brain, signaling Blood-Brain Barrier breakdown and active inflammation.

Many clinical drug trials are designed based on the assumption that lesion enhancement on MRI remains visible on average for 1 month. For practical reasons, few serial MRI studies of patients with MS have been performed at intervals shorter than 4 weeks.

Methods
The authors performed a year-long longitudinal study in 26 patients with Relapsing/Remitting MS (RRMS).

Which, comprised an initial phase of MRI follow-up at weekly intervals for 8 weeks, followed by imaging every other week for another 16 weeks, and monthly thereafter.

They present a quantitative analysis (using a supervised interactive thresholding procedure) of new enhancing lesions appearing during the first 6 weeks in this cohort and evaluated from the time of first detection until enhancement was no longer seen.

Results
The average duration of Gd-DTPA enhancement in individual new lesions was 3.07 weeks (median, 2 weeks).

Significant correlations were demonstrated between the duration of contrast enhancement or initial growth rates and lesion volumes.

Different lesions in the same patient appeared to develop largely independent of each other and demonstrated a large range in the duration of enhancement during the acute phase of their evolution.

Conclusions
The average duration of Blood-Brain Barrier impairment in RRMS is shorter than earlier estimates. Early lesion growth parameters may predict final lesion size.

Within-patient heterogeneity of lesion evolution suggests that individual lesions develop independently.

Background And Purpose
Injury to deep Gray Matter structures in Multiple Sclerosis (MS) has been suggested by recent NeuroImaging and NeuroPathology studies.

Diffusion-weighted Magnetic Resonance Imaging (DWI) can assess tissue damage with greater sensitivity than conventional MRI.

The authors' objective was to assess Thalamic Gray Matter damage by Diffusion-weighted imaging in MS patients.

Methods
This was a retrospective study performed at a tertiary care, University-affiliated comprehensive MS center of 82 MS patients and 43 controls.

The main outcome measures were Thalamic Apparent Diffusion Coefficients (ADCs), Whole-Brain Atrophy (Brain Parenchymal Fraction), Fluid-Attenuated Inversion Recovery (FLAIR) hypertense lesion volume, and clinical course.

Results
ADCs in the Left Thalamus were higher in MS patients (0.741 +/- 0.044 x 10(-3) mm2/s) than controls (0.723 +/- 0.036 x 10(-3) mm2/s) (P = .027).

And higher in Secondary/Progressive MS patients (0.761 +/- 0.044 x 10(-3) mm2/s), than Relapsing/Remitting MS patients (0.735 +/- 0.032 x 10(-3) mm2/s) (P = .029).

ADCs in the Right Thalamus were higher in Secondary/Progressive MS patients (0.784 +/- 0.069 x 10(-3) mm2/s) than controls (0.757 +/- 0.038 x 10(-3) mm2/s) (P = .033).

In the MS group:
1. Left Thalamus ADCs correlated negatively with Brain Parenchymal Fraction (r = -0.30, P = .008)
2. Total Left Hemispheric FAIR lesion volume correlated with ADCs in the:
   • Left (r = 0.35, P = .001)
   • Right (r = 0.39, P < .001) Thalamus
3. Total Right Hemispheric FLAIR lesion volume correlated with ADCs in the:
   • Left (r = 0.31, P = .006)
   • Right Thalamus (r = 0.22, P = .048).

And total Right Hemispheric FLAIR lesion volume correlated with ADCs in the Left (r = 0.31, P = .006) and Right Thalami (r = 0.22, P = .048).

Conclusions
MS patients have increased water Diffusion in the Thalamus that is partly associated with clinical course, lesion load, and Whole-Brain Atrophy.

Both indirect and direct mechanisms of Gray Matter injury may play a role in the pathophysiology of MS.

Despite patients with Primary/Progressive Multiple Sclerosis (PPMS) experience a Progressive disease course from onset, the burden and activity of lesions on conventional Magnetic Resonance Imaging (MRI) scans of the Brain are lower than in all other main clinical phenotypes of MS.

This review outlines the major contributions given by Magnetization Transfer MRI, Diffusion Tensor MRI and Functional MRI to the understanding of the pathophysiology of PPMS.

And, provides evidence that, at least, three factors might explain this clinical/MRI discrepancy:
1. Presence of diffuse tissue damage at a microscopic level
2. Prevalent involvement of the Cervical Cord
3. Impairment of the adaptive capacity of the Cortex
   • Limit the functional consequences of SubCortical damage

T₁ Black Holes (BHs) on MRIs may represent either areas of Edema or Axonal loss in patients with Multiple Sclerosis.

BHs begin as Contrast Enhancing Lesions (CELs) and evolve differently from patient to patient, and within the same patient over time.

We analyzed BHs formation over a 4-year period. Forty-eight monthly MRIs of nine non-treated Multiple Sclerosis patients were evaluated for numbers of CELs and BHs.

A BH was defined as a HypoIntense lesion on a T₁ pre-contrast image that coincided with a region of high signal intensity on the T₂-weighted images.

A BH was considered as Acute (ABH) when it occurred coincidently with the presence of enhancement and as Persisting (PBH) when present after the cessation of enhancement.

The present study aimed to analyze the:
1. Incidence of CELs, new PBHs, and the accumulation of PBHs
2. Relationship between the quantity of CELs in a given month and,
   • Likelihood of accumulating PBHs in the subsequent month
3. Relationship between the duration of CELs and PBHs

Pitman's correlation test evaluated the effect of time on either the increase of CELs and new PBHs or the accumulation of PBHs.

While a multiple logistic regression analysis evaluated the relationship between progression of time and CELs, and the increase of PBHs in a multivariate model.

The relationship between the enhancing lesions duration and the PBHs duration, or the time to revert back to an IsoIntense lesion was analysed using Kaplan-Meier survival models.

PBHs accumulated (P < 0.001) in all patients, but the formation of new PBHs increased in four patients (P < or = 0.007) in conjunction with an increase in either the quantity of CELs (P < 0.001, for two patients) or the proportion of CELs turning into PBHs (P < or = 0.02, for two patients).

Logistic regression analysis showed that neither progression of time nor the number of CELs in a given month were able to predict the probability of increasing the number of PBHs in the subsequent month in any patient. Out of 397 ABHs, 55.7% evolved to a PBH.

The duration of PBHs correlated with the duration of enhancement. PBHs preceded by CELs observable on a single MRI persisted for a shorter time (P < 0.002) than those preceded by CELs visible on > or =2 monthly MRIs.

The formation of a new PBH was found to be related to CELs activity; however, duration of PBHs is most likely a consequence of the duration of the enhancement.

Background
Magnetization Transfer Ratio (MTR) Histogram analysis provides a global measure of disease burden in Multiple Sclerosis (MS).

MTR abnormalities in Normal-Appearing Brain Tissue (NABT) provide quantitative information on the extent of tissue damage undetected by conventional T₂-weighted (T₂W) Magnetic Resonance Imaging (MRI).

Aims
1) To compare the MTR Histograms from NABT across a broad spectrum of relapse onset MS patients, including Relapsing/Remitting (RR) MS (including newly diagnosed and Benign subgroups) and Secondary/Progressive (SP) MS.

2) To determine the relationship between clinical disability and NABT MTR Histograms.

Methods
2D Spin Echo Magnetization Transfer Imaging was performed on 70 RRMS and 25 SPMS patients and compared with 63 controls.

MTR Histograms were acquired for NABT after extracting lesions and CerebroSpinal Fluid (CSF). T₂W images were used to measure the Brain Parenchymal Fraction (BPF) and T₂ lesion load.

Results
MS patients had a disease duration ranging from 0.5 to 37 years and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 8.5.

There was a significant decrease in NABT mean MTR (+/- standard deviation) compared with controls (33.07 pu +/- 1.06 versus 34.26 pu +/- 0.47; P < 0.001) with an effect size of 2.56.

The reduction in NABT mean MTR varied among patient groups from 4.9% for SPMS, 3% for all RRMS, 2.7% for early RRMS and 2.5% for Benign MS, compared with controls.

NABT mean MTR correlated significantly with T₂ lesion load (r = -0.82) and BPF (r = 0.58).

EDSS score correlated with NABT mean MTR (r = -0.43), BPF (r = -0.33) and with T₂ lesion load (r = 0.59).

Multivariate analysis using NABT MTR peak height, T₂ lesion load and BPF combined only accounted for 38% of the variance in the EDSS (r = 0.62; P < 0.001). Disease duration accounted for an additional 14% of variance in the EDSS (r = 0.72; P < 0.001).

Conclusions
There is evidence of diffuse abnormalities in NABT in addition to global Brain Atrophy in relapse onset MS patients, including those with recently diagnosed RRMS and Benign MS.

The abnormalities are greatest in patients with the more disabling SPMS. Atrophy, NABT and lesion abnormalities are all partly correlated.

The processes marked by these MR measures all contribute to disability in MS, providing complementary information relevant to the complex pathological processes that occur in MS.

Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS.

Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space.

Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation.

Prospective studies have shown that the presence of such lesions predicts future conversion to Clinically Definite (CD) MS.

Indeed, in a young to middle-aged adult with a Clinically Isolated Syndrome (CIS), once alternative diagnoses are excluded at baseline.

The finding of three or more White Matter lesions on a T₂-weighted MRI scan (especially if one of these lesions is located in the PeriVentricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years.

Moreover, the presence of two or more Gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T₂ lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term.

By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.